The human papillomaviruses have been associated with several genital tract cancers. Over 70 different papillomaviruses (HPVs) have now been identified. Approximately 25 of these are associated with genital tract lesions. The HPVs that affect the anogenital area can be separated on the basis of their clinical associations into two distinct groups. One group, including HPV-6 and HPV-11, is generally associated with benign anogenital warts that infrequently progress to cancer and is referred to as "low risk" viruses. The "high risk" group, including HPV-16 and HPV-18, is associated with intraepithelial neoplastic lesions that are at high risk for malignant progression. The laboratory has been studying the role that HPV may play in the progression of a benign lesion to a malignant lesion. In HPV-16 and HPV-18 associated human cancers, the viral genome is generally found to be integrated. Integration often occurs in the E1 or E2 open reading frame, such that it disrupts the expression of the E2 open reading frame. The E1 and E2 open reading frames of the papillomaviruses encodes DNA binding proteins that are involved in the DNA regulation and regulation of viral promoters. Integration into the E1 or E2 genes leads to an increase in the immortalization capacity of the viral genome. The E6 and E7 ORFs of HPV-16 and HPV-18 have been shown to encode transforming proteins. Expression of both the E6 and E7 gene products are required for efficient immortalization of human keratinocytes. The E7 proteins of the genital tract HPVs have been shown to associate with the product of the retinoblastoma tumor susceptibility gene. The E6 protein of the "high risk" genital HPVs can complex with the p53 cellular protein, which is also a tumor suppressor gene. The biochemistry of these interactions has been a major focus of this project. An additional cellular factor referred to as E6AP (E6 associated protein) has recently been identified.